Industrial wastewaters rich in organic carbon have potential for value generation, but conventional, low-rate, anaerobic–aerobic wastewater treatment (WWT) processes often incur significant capital expenses and energy consumption. In this study, we leveraged experimental data for biorefinery-derived wastewaters to characterize the implications of transitioning from a conventional, low-rate process to a high-rate, multistage anaerobic process. We designed and simulated these WWT processes across seven first- and second-generation (1G/2G) biorefineries and evaluated the implications for biorefinery sustainability through techno-economic analysis (TEA) and life cycle assessment (LCA). Compared to the conventional design, the new process can substantially reduce capital costs and electricity usage. These improvements were particularly evident for 2G biorefineries, translating to 5%–13% lower minimum product selling prices (MPSPs) and 7%–135% lower 100-year global warming potentials (GWPs; the 135% reduction is due to the transition of one biorefinery from net emission [0.87 kg of CO2e·gal–1] to net sequestration [−0.31 kg of CO2e·gal–1]). Biorefineries could further reduce the MPSP through the renewable identification number (RIN) credits by upgrading and selling the biogas as renewable natural gas, but at the expense of increasing GWP. When normalized, the COD management cost ranged from $–56 to $465 per tonne of COD, indicating that wastewater could be a net source of revenue for some biorefineries.